Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically target metastatic disease. Many of the current in vitro models of metastasis focus on the molecular mechanisms of migration, invasion and/or surviving anoikis, but cannot recapitulate the complexity of the environment in which metastasis occurs in vivo. Conversely, in mouse models of metastasis, it has been difficult to examine the molecular mechanisms that enable cells to proceed through each distinct step of metastasis. For these reasons little is known about the challenges facing metastasizing cells in vivo, and how they are overcome. My proposal utilizes a clinically relevant model of melanoma metastasis, patient-derived xenografts in immunocompromised mice, to dissect the metastatic cascade into distinct steps. During the mentored phase of the grant, I will focus on identifying metabolic and stress-response signaling pathways that are specific to melanoma cells at different stages of metastasis, and functionally validate their importance. With these insights, I will continue independent research focusing on the molecular details of the pathways that are engaged during these bottlenecks to identify novel therapeutic targets that may prove useful in treating metastatic disease.